Research Interests

Approaches

The laboratory studies human diseases using a multidisciplinary approach. We have expertise in human and mouse immunology, cellular immunology, T cell repertoire analysis and signal transduction. Furthermore, many of our studies are done in collaborations with other laboratories to take advantage of the expertise necessary to dissect in a comprehensive manner the molecular mechanisms underlying different disease processes, in particular autoimmunity, inflammatory bowel disease and infectious diseases. The multidisciplinary approach is also illustrated by the diversity of the group of young investigators working in the laboratory.

Research Proposal

My laboratory has a longstanding interest on the interplay between innate and adaptive immunity and the mechanisms underlying immune-mediated tissue destruction, with a particular emphasis on autoimmune diseases and mucosal immunity. We study celiac disease as a organ-specific autoimmune disease model to dissect the crosstalk between immune cells and tissues. Celiac disease is a T-cell mediated intestinal disease induced by gluten, a protein present in wheat, in HLA-DQ2 or -DQ8 individuals. We have identified a regulatory loop whereby stressed or infected tissue epithelial cells literally arm cytolytic T cells (CTL) to kill them, through the interplay of the cytokine IL-15, activating receptors of the natural killer (NK) family and the stress-induced MHC-like ligands MIC and HLA-E. This innate tissue-mediated control of effector CTL constitutes a new layer of immune regulation with implications for autoimmune disease mechanisms and treatments, which we study at the cellular and molecular level (Fig. 1).

Figure 1

We have an ongoing collaboration with Dr. Teyton to determine the structural basis for the association of HLA-DQ8 with celiac disease. We have a multi-center translational research program aimed at analyzing the early events in celiac disease and type-1 diabetes. We are currently collaborating with Drs. Winchester and FitzGerald and on the pathogenesis of rheumatoid and psoriatic arthritis. Finally, we have developed multiple transgenic and knockout mouse models allowing us to further analyze the role of IL-15 and NK receptors in tissue immunity and disease, in particular celiac disease, type 1 Diabetes and tumor immunity.

More recently, the laboratory has developed a strong interest in immune regulation and host/pathogen interactions. Ongoing project comprise the innate mechanisms underlying the induction of tolerogenic dendritic cells, type 1 regulatory IL-10 producing T cells and the regulation of natural regulatory T cells. We use as experimental mouse models of oral tolerance, inflammatory bowel diseases and yersinia infection.